Epilepsy is a relatively common neurological condition affecting 0.4–1% of the world's population (45–100 million people). For the general population there are approximately 20–70 new cases per 100,000 diagnosed each year with a 3–5% lifetime probability of developing the disease. The older established antiepileptic drugs (AEDs) phenyloin, carbamazepine, clonazepam, ethosuximide, valproic acid and barbiturates are widely prescribed but suffer from a range of side effects. Furthermore, there is a significant group of patients (20–30%) that are resistant to the currently available therapeutic agents. Since 1989 several new drugs have been launched, including felbamate, gabapentin, lamotrigine, oxcarbazepine, tiagabine, topimarate, vigabatrin, zonisamide and levetiracetam. While many of the new AEDs show improved efficacies and side-effect profiles, patients with intractable epilepsy remain untreated. There is clearly a need for improved medications (Cosford N. D. P. et al., Annual Reports in Medicinal Chemistry (1998), 33, 61–70).
U.S. Pat. No. 6,066,666 reports lactam and thiolactam derivatives having useful anticonvulsant and anxiolytic activity, and thus being effective in the treatment of epilepsy.
U.S. Pat. No. 5,334,720 relates to diphenyl-1-(aminoalkyl)-2-piperidone and -2-pyrrolidinone derivatives, which possess anticonvulsant properties and are useful anti-epileptic agents.
European Patent No. 0 162 036 B1 discloses levetiracetam or (S)-(−)-α-ethyl-2-oxo-1-pyrrolidineacetamide as well as its use as a protective agent for the treatment and the prevention of hypoxic and ischemic type aggressions of the central nervous system. This compound is also effective in the treatment of epilepsy, a therapeutic indication for which it has been demonstrated that its dextrorotatory enantiomer (R)-(+)-α-ethyl-2-oxo-1-pyrrolidineacetamide completely lacks activity (Gower A. J. et al., Eur. J. Pharmacol. (1992), 222, 193–203). In the European Patent No. 0 645 139 B1, levetiracetam has been disclosed for its anxiolytic activity. International Patent Application No. PCT/EP00/11808 discloses the use of levetiracetam for the curative and/or prophylactic treatment of bipolar disorders, migraine, chronic or neuropathic pain as well as combinations of levetiracetam with at least one compound inducing neural inhibition mediated by GABAA receptors.
Continuing its research work in the field of the treatment of epilepsy, the applicant discloses now new 2-oxo-piperidinyl- and 2-oxo-azepanyl alkanoic acid derivatives. These new 2-oxo-piperidinyl- and 2-oxo-azepanyl alkanoic acid derivatives are useful for the prevention or the treatment of epilepsy, epileptogenesis, seizure disorders and convulsions.
These compounds may also be used for the treatment of other neurological disorders including bipolar disorders, mania, depression, anxiety, migraine, trigeminal and other neuralgia, chronic pain, neuropathic pain, cerebral ischemia, cardiac arrhythmia, myotonia, cocaine abuse, stroke, myoclonus, essential tremor and other movement disorders, neonatal cerebral haemorrhage, amyotrophic lateral sclerosis, spasticity, Parkinson's disease and other degenerative diseases.
In addition the compounds according to the invention may be used in the treatment of bronchial asthma, asthmatic status and allergic bronchitis, asthmatic syndrome, bronchial hyperreactivity and bronchospastic syndromes as well as allergic and vasomotor rhinitis and rhinoconjunctivitis.